KR102307852B1 - Composition for enhancing transdermal absorption of drug and patch preparation - Google Patents

Abstract

The present invention provides a composition for accelerating the percutaneous absorption of a drug comprising a polyhydric alcohol having 3 to 8 carbon atoms, an organic acid having 2 to 20 carbon atoms, and a higher alcohol having 12 to 20 carbon atoms, and a support comprising the composition on one side of the support It relates to a patch formulation comprising a drug-containing pressure-sensitive adhesive layer.

Description

Composition and patch preparation for promoting transdermal absorption of drugs

The present invention relates to a composition for promoting the transdermal absorption of a drug that exhibits an excellent effect of accelerating the transdermal absorption of the drug.

As a drug administration method for the purpose of systemic action, in general, oral administration and injection are widely adopted. In oral administration, metabolism in the liver (first-pass effect) is unavoidable, and in administration by injection, a drug having a short biological half-life requires frequent administration, so that the drug blood concentration cannot be easily maintained. On the other hand, the transdermally absorbed formulation can overcome the above-mentioned drawbacks, maintain a stable drug blood concentration, reduce the number of administrations, improve compliance, and facilitate discontinuation of administration. It is advantageous in terms of

However, since many drugs have low transdermal absorption, there are not many drugs actually formulated as transdermal preparations, so a means for increasing the transdermal absorption of the drug is required. Therefore, it has been generally attempted to add a transdermal absorption enhancer as a base. For example, WO2000/53226 discloses that a composition containing a fatty acid having 8 to 15 carbon atoms or a higher alcohol having 8 to 12 carbon atoms and a polyhydric alcohol as a composition for promoting transdermal absorption improves the transdermal absorption of a drug. Further, JP-A-5-946 discloses that a composition containing a fatty acid having 8 to 12 carbon atoms or an aliphatic alcohol and a polyhydric alcohol improves the percutaneous absorption of a drug.

However, according to the studies of the present inventors, such conventional compositions that are said to improve the transdermal absorption of drugs cannot provide stable transdermal absorption because the composition changes due to the volatilization of the solvent, or the transdermal absorption of only certain drugs. Since the accelerating effect was exhibited or the application to the non-aqueous adhesive patch was difficult, there were few exhibiting a sufficiently excellent absorption accelerating effect and versatility.

The present invention has been made by examining the above-mentioned circumstances, and an object of the present invention is to provide a composition for promoting the transdermal absorption of a drug and a patch preparation having excellent transdermal absorption of the drug, which exhibit an excellent effect of accelerating the transdermal absorption of the drug.

As a result of intensive research conducted by the present inventors to solve the above problems, the combination of a polyhydric alcohol having 3 to 8 carbon atoms, an organic acid having 2 to 20 carbon atoms and a higher alcohol having 12 to 20 carbon atoms is very advantageous for improving the percutaneous absorption of drugs. found to work. The present inventors have completed the present invention by further conducting research based on the above findings.

Accordingly, the present invention provides the following.

[1] A composition for promoting percutaneous absorption of a drug, comprising a polyhydric alcohol having 3 to 8 carbon atoms, an organic acid having 2 to 20 carbon atoms and a higher alcohol having 12 to 20 carbon atoms.

[2] The composition of the above [1] for promoting percutaneous absorption of a basic drug.

[3] The above [1] or [2], wherein the higher alcohol having 12 to 20 carbon atoms is at least one selected from the group consisting of lauryl alcohol, myristyl alcohol, hexyldecanol, oleyl alcohol and octyldodecanol. composition.

[4] The composition according to any one of [1] to [3], wherein the organic acid having 2 to 20 carbon atoms is an organic acid having 2 to 8 carbon atoms.

[5] The composition of the above [4], wherein the higher alcohol having 12 to 20 carbon atoms is a higher alcohol having 12 to 18 carbon atoms.

[6] The composition according to any one of [1] to [3], wherein the organic acid having 2 to 20 carbon atoms is an organic acid having 12 to 20 carbon atoms.

[7] The composition of the above [6], wherein the higher alcohol having 12 to 20 carbon atoms is a higher alcohol having 14 to 20 carbon atoms.

[8] The composition according to any one of [1] to [7] above, for use in a patch formulation.

[9] A patch preparation comprising a support and a drug-containing pressure-sensitive adhesive layer or drug storage layer comprising the composition of any one of [1] to [7] and a drug on one side of the support.

[10] The patch formulation of the above [9], wherein the drug is a basic drug.

The composition for promoting percutaneous absorption of a drug of the present invention exhibits excellent transdermal absorption promoting effect for acidic drugs and basic drugs. By using such a composition, it is possible to realize a matrix-type or reservoir-type patch preparation showing excellent percutaneous absorption of the drug. In particular, when the drug is a basic drug, the effect is remarkable.

BRIEF DESCRIPTION OF THE DRAWINGS It is a schematic sectional drawing of one Embodiment of the matrix-type patch preparation of this invention.
It is a schematic sectional drawing of one Embodiment of the reservoir type|mold patch formulation of this invention.
1, 1 is a release liner, 2 is a drug-containing adhesive layer, 2' is an adhesive layer, 3 is a drug permeation control membrane, 4 is a drug storage layer, 5 is a support.

Hereinafter, the present invention will be described with reference to preferred embodiments thereof.

The composition for accelerating the percutaneous absorption of a drug of the present invention (hereinafter simply referred to as "the composition of the present invention") mainly contains a polyhydric alcohol having 3 to 8 carbon atoms, an organic acid having 2 to 20 carbon atoms and a higher alcohol having 12 to 20 carbon atoms.

As the polyhydric alcohol having 3 to 8 carbon atoms, dihydric or trihydric alcohols can be used, and the structure is not particularly limited. Specific examples include propylene glycol, butylene glycol, glycerol, dipropylene glycol, octanediol, and the like. Among these, those having 3 or 4 carbon atoms are preferable, and propylene glycol and butylene glycol are particularly preferable. One or more of these polyhydric alcohols having 3 to 8 carbon atoms can be used.

As the higher alcohol having 12 to 20 carbon atoms, the structure is not particularly limited, and any higher alcohol can be used. For example, any of straight-chain and branched-chain higher alcohols which may have one or more unsaturated bonds may be used. Specific examples thereof include lauryl alcohol, myristyl alcohol, cetyl alcohol, hexyldecanol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, arachyl alcohol, octyldodecanol and the like. Of these, lauryl alcohol, myristyl alcohol, hexyldecanol, oleyl alcohol and octyldodecanol are preferable, and lauryl alcohol and oleyl alcohol are particularly preferable. A higher alcohol having 17 to 19 carbon atoms, such as oleyl alcohol, is particularly preferable because the effect of promoting percutaneous absorption can be obtained regardless of the type of organic acid. One or more of these higher alcohols having 12 to 20 carbon atoms can be used.

As the organic acid having 2 to 20 carbon atoms, a monovalent, divalent or trivalent organic acid can be used, and the structure thereof is not particularly limited, and any organic acid can be used. Specific examples thereof include acetic acid, lactic acid, tartaric acid, citric acid, benzoic acid, caproic acid, enantic acid, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, arachidic acid acetic acid, lactic acid, tartaric acid, citric acid, benzoic acid, myristic acid, isostearic acid and oleic acid are preferred. One or more of these organic acids having 12 to 20 carbon atoms can be used.

Among the organic acids having 2 to 20 carbon atoms, the organic acid having 2 to 8 carbon atoms is used in combination with a higher alcohol having 12 to 19 carbon atoms (for example, lauryl alcohol, myristyl alcohol, hexyldecanol, oleyl alcohol, etc.) to promote percutaneous absorption. It is preferable because it is excellent in an effect. Here, the higher alcohol having 12 to 19 carbon atoms is preferably lauryl alcohol or oleyl alcohol, particularly preferably lauryl alcohol.

In addition, an organic acid having 12 to 20 carbon atoms (especially an organic acid having 14 to 20 carbon atoms) is used in combination with a higher alcohol having 14 to 20 carbon atoms (eg, myristyl alcohol, hexyldecanol, oleyl alcohol, octyldodecanol, etc.). It is preferable because it is excellent in the effect of accelerating percutaneous absorption. Here, the higher alcohol having 14 to 20 carbon atoms is preferably hexyldecanol, oleyl alcohol or octyldodecanol.

The composition of the present invention can promote the percutaneous absorption of various drugs. Therefore, whether the drug is a basic drug or an acidic drug, a pharmaceutical composition having excellent transdermal absorption can be prepared by combining it with the composition of the present invention. Since the organic acid exhibits an action of increasing the solubility of the drug in the formulation and in the skin, and the effect of promoting percutaneous absorption can be further improved, it is preferable to combine it with a basic drug. That is, by combining the composition of this invention with the basic compound or its salt used as an active ingredient of various pharmaceuticals, the pharmaceutical composition excellent in percutaneous absorption can be manufactured. A basic drug means a drug that has a basic functional group such as an amino group (1st class, 2nd class or tertiary) in a molecule and shows basicity as a compound, and an acidic compound has an acidic functional group such as a carboxyl group in a molecule and is acidic as a compound means In addition, the drug is not particularly limited as long as it has the property of being able to be administered through the skin of mammals such as humans, that is, percutaneous absorption.

Specific examples of the drug include general anesthetics, hypnotic sedatives, antiepileptic drugs, antipyretic analgesics, anti-inflammatory drugs, antispasmodics, psychiatric drugs, local anesthetics, skeletal muscle relaxants, autonomic drugs, antispasmodics, antiparkinson drugs, antihistamines, and psychiatric drugs. , Arrhythmic drugs, diuretics, blood pressure lowering drugs, vasoconstrictors, vascular dilators, peripheral vasodilators, arteriosclerosis drugs, circulatory drugs, respiratory stimulants, antitussive expectorants, hormonal drugs, external drugs for purulent diseases, Pain-relieving-hemostasis anti-inflammatory drug, parasitic skin disease drug, hemostasis drug, gout treatment drug, diabetes drug, anti-malignant tumor drug, antibiotic, chemotherapeutic drug, narcotic, anti-integration drug, anti This includes antidepressants and smoking cessation aids.

The content of each component in the composition of the present invention may be appropriately determined according to conditions such as the type of drug and the desired percutaneous absorption rate. Generally, in 100 parts by weight of the total weight of polyhydric alcohol, higher alcohol and organic acid, 40 to 99.9 parts by weight of polyhydric alcohol, preferably 50 to 99 parts by weight, more preferably 60 to 98 parts by weight, even more preferably It is preferable that 70 to 98 parts by weight, particularly preferably 80 to 98 parts by weight, and most preferably 90 to 97 parts by weight, the remainder being higher alcohols and organic acids. The mixing ratio of the higher alcohol and the organic acid (higher alcohol: organic acid) is preferably 0.01:99.99 to 99.99:0.01 by weight, more preferably 0.1:99.9 to 99.9:0.1, particularly preferably 1:99 to 99:1, Most preferably, it is 30:70 to 70:30.

The composition of the present invention is used in the preparation of a transdermally absorbed preparation together with a drug. Examples of the formulation of the transdermally absorbable preparation include ointments, creams, liquids, lotions, liniments, poultices, plasters, patches, and the like. In many cases, the composition of the present invention is formulated as a drug-containing composition further containing a drug. From the viewpoint of the effect of accelerating the transdermal absorption of the drug, the content of the drug in the drug-containing composition is preferably a saturated concentration or 80% by weight or more of the saturated concentration. Although the specific amount varies depending on the type of drug, the amount of the drug is 0.1 to 40 parts by weight, preferably 0.5 to 35 parts by weight, more preferably 1.0 to 30 parts by weight based on 100 parts by weight of the total weight of the polyhydric alcohol, higher alcohol and organic acid. It is preferable to contain.

Hereinafter, a patch formulation using the composition of the present invention will be described.

The patch formulation of the present invention may be a so-called matrix-type patch formulation having a drug-containing pressure-sensitive adhesive layer on one side of the support, or a so-called reservoir-type patch formulation having an adhesive layer and a drug storage layer on one side of the support.

< Matrix-type patch formulation >

1 shows a typical example of the matrix-type patch formulation of the present invention, wherein a drug-containing pressure-sensitive adhesive layer 2 and a release liner 1 are laminated on one side of a support 5 in this order. In the matrix-type patch preparation, a drug-containing pressure-sensitive adhesive layer containing the composition of the present invention is formed on one side of a support.

The drug-containing adhesive layer

In the drug-containing composition prepared by adding a drug to the composition of the present invention, about 40 to 1900 parts by weight (preferably about 67 to 900 parts by weight) of the adhesive polymer, based on the drug-containing composition (100 parts by weight), as needed a step of preparing a composition for forming a pressure-sensitive adhesive layer by mixing an appropriate amount of a solvent and, if necessary, a plasticizer to be described later;

forming a laminate by applying the composition for forming a pressure-sensitive adhesive layer on one side of a support or a release treatment side of a release liner; and

It may be formed through a process of drying the laminate. Although the solvent is not specifically limited, Ethyl acetate, toluene, hexane, etc. are preferable. The drug-containing pressure-sensitive adhesive layer may be cross-linked, and in this case, a cross-linking agent may be further added to the composition for forming the pressure-sensitive adhesive layer. The composition for forming the pressure-sensitive adhesive layer may be applied to one side of the support or the release liner by, for example, casting, printing, and other techniques known per se to those skilled in the art. After formation of the drug-containing pressure-sensitive adhesive layer, it is preferable to attach a release liner or a support for protection, preservation, and the like of the drug-containing pressure-sensitive adhesive layer.

The adhesive polymer is not particularly limited, and an acrylic polymer containing a (meth)acrylic acid ester-based polymer; rubber-based polymers such as styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, polyisoprene, polyisobutylene, polybutadiene and the like; silicone-based polymers such as silicone rubber, dimethylsiloxane base, diphenylsiloxane base, and the like; vinyl ether polymers such as polyvinyl methyl ether, polyvinyl ethyl ether, polyvinyl isobutyl ether, and the like; vinyl ester polymers such as vinyl acetate-ethylene copolymer and the like; ester polymers composed of a carboxylic acid component such as dimethyl terephthalate, dimethyl isophthalate, dimethyl phthalate and the like and a polyhydric alcohol such as ethylene glycol and the like can be mentioned. Among these, an acrylic polymer is preferable from the viewpoint of compatibility with polyhydric alcohol.

The acrylic polymer is preferably obtained by copolymerizing a (meth)acrylic acid alkyl ester and a functional monomer as a main component. That is, a copolymer comprising 50 to 99% by weight (preferably 60 to 95% by weight) of a monomer component composed of a (meth)acrylic acid alkyl ester and the remaining monomer component is a functional monomer is preferred. Here, the main component means a monomer component contained in a proportion of 50% by weight or more of the total weight of the monomer components constituting the copolymer.

(Meth) acrylic acid alkyl esters (hereinafter also referred to as main component monomers) are generally linear or branched alkyl groups having 4 to 13 carbon atoms (eg, butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl). , undecyl, dodecyl, tridecyl, etc.), and one or more of these are used.

The functional monomer has at least one unsaturated double bond in the molecule involved in the copolymerization reaction and has a functional group in the side chain. Examples thereof include carboxyl group-containing monomers such as (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride and the like, hydroxyl group-containing monomers such as (meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid hydroxypropyl ester and the like; sulfoxyl group-containing monomers such as styrene sulfonic acid, allyl sulfonic acid, sulfopropyl (meth)arylate, (meth)acryloyloxynaphthalene sulfonic acid, and acrylamide methylpropane sulfonic acid; amino group-containing monomers such as (meth)acrylic acid aminoethyl ester, (meth)acrylic acid dimethylaminoethyl ester, (meth)acrylic acid tert-butylaminoethyl ester and the like; amide group-containing monomers such as (meth)acrylamide, dimethyl (meth)acrylamide, N-methylol (meth)acrylamide, N-methylolpropane (meth)acrylamide, and N-vinylacetamide; (meth)acrylic acid methoxyethyl ester, (meth)acrylic acid ethoxyethyl ester, (meth)acrylic acid methoxyethylene glycol ester, (meth)acrylic acid methoxydiethylene glycol ester, (meth)acrylic acid methoxypolyethylene glycol ester, (meth)acrylic acid methoxypolyethylene glycol ester ) alkoxy group-containing monomers such as acrylic acid methoxypolypropylene glycol ester, (meth)acrylic acid tetrahydrofuryl ester, and the like.

One or more of these functional monomers may be used. Among these, from the viewpoints of the pressure-sensitive adhesiveness of the pressure-sensitive adhesive layer, cohesiveness, and the release property of the drug contained in the pressure-sensitive adhesive layer, carboxyl group-containing monomers are preferred, and (meth)acrylic acid is particularly preferred.

As the acrylic polymer, one obtained by further copolymerizing another monomer with a copolymer of the above (meth)acrylic acid alkyl ester (main component monomer) and a functional monomer may be used.

Examples of such other monomers are (meth)acrylonitrile, vinyl acetate, vinyl propionate, N-vinyl-2-pyrrolidone, methylvinylpyrrolidone, vinylpyridine, vinylpiperidone, vinylpyrimidine, vinylpiperazine, vinylpyrrole, vinylimidazole, vinylcaprolactam, vinyloxazole, and the like. One or more of these can be used.

The amount of these other monomers to be used is generally preferably about 0 to 40% by weight, more preferably about 10 to 30% by weight, based on the total weight of the (meth)acrylic acid alkyl ester (main component monomer) and the functional monomer.

As the acrylic polymer, the adhesiveness to human skin is good and adhesion and peeling can be easily repeated. Ternary copolymers are preferred, 2-ethylhexyl acrylate, acrylic acid and N-vinyl-2-pyrrolidone 40-99.8:0.1-10:0.1-50, preferably 50-89:1-8: A copolymer obtained by copolymerization in a weight ratio of 10 to 40 is more preferable.

The rubber-based polymer is selected from polyisobutylene, polyisoprene and styrene-diene-styrene block copolymers (styrene-butadiene-styrene block copolymer (SBS), styrene-isoprene-styrene block copolymer (SIS), etc.) as the main component. It is preferable to contain 1 or more types used. A mixture of a high molecular weight polyisobutylene having a viscosity average molecular weight of 500,000 to 2,100,000 and a low molecular weight polyisobutylene having a viscosity average molecular weight of 10,000 to 200,000 (95 by weight) because of high drug stability and the ability to simultaneously achieve the required adhesive and cohesive strength :5 to 5:95) is particularly preferred.

In the case of using a rubber-based polymer, it is preferable to further add a tackifier because it is possible to improve the adhesion of the drug-containing pressure-sensitive adhesive layer at room temperature. The tackifier is not particularly limited, and those known in the art may be appropriately selected and used. Examples thereof include petroleum-based resins (eg, aromatic petroleum resins, aliphatic petroleum resins, etc.), terpene-based resins, rosin-based resins, coumarone indene resins, styrene-based resins (eg, styrene resins, poly(α-methylstyrene)) etc.), hydrogenated petroleum resins (eg, alicyclic saturated hydrocarbon resins, etc.) and the like. Of these, alicyclic saturated hydrocarbon resins are preferable because the stability of the drug is improved. One or more tackifiers can be used in combination, and the amount of the tackifier is generally 33 to 300 wt%, preferably 50 to 200 wt%, based on the total weight of the rubber-based polymer.

In the patch formulation of the present invention, the content of the composition for promoting percutaneous absorption of the drug of the present invention in the drug-containing adhesive layer is preferably 5 to 70% by weight, more preferably 10 to 60% by weight of 100% by weight of the drug-containing adhesive layer. %am.

If desired, the drug-containing pressure-sensitive adhesive layer further contains a plasticizer. The plasticizer is not particularly limited as long as it plasticizes the pressure-sensitive adhesive to impart a soft feeling to the pressure-sensitive adhesive layer and reduces pain or skin irritation caused by skin adhesion when the patch formulation is peeled off the skin. When a plasticizer is added to the drug-containing pressure-sensitive adhesive layer, the plasticizer is added to the composition together with the composition of the present invention when preparing the composition for forming the pressure-sensitive adhesive layer. The plasticizer is preferably added in a proportion of 1 to 70% by weight, more preferably 20 to 60% by weight of 100% by weight of the drug-containing pressure-sensitive adhesive layer.

Preferred examples of the plasticizer include oils and fats such as olive oil, castor oil, squalene and lanolin, decylmethyl sulfoxide, methyloctyl sulfoxide, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, methylpyrrolidone, and dodecylpyrrolidone. Organic solvents, surfactants such as polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, phthalic acid esters such as dibutyl phthalate, diheptyl phthalate, dioctyl phthalate, diethyl sebacate, Sebacate esters such as dibutyl sebacate and dioctyl sebacate, hydrocarbons such as liquid paraffin, ethyl oleate, diisopropyl adipate, isopropyl palmitate, octyl palmitate, isopropyl myristate, fatty acid esters such as isotridecyl myristate and ethyl laurate, fatty acid esters of glycerin, propylene glycol fatty acid esters, ethoxylated stearyl alcohol, pyrrolidone carboxylic acid fatty acid esters, and the like. Any 1 type of these can be used individually or in combination of 2 or more types.

A cross-linked structure may be introduced into the drug-containing pressure-sensitive adhesive layer. In this case, the drug-containing pressure-sensitive adhesive layer is subjected to physical crosslinking treatment by irradiation with ultraviolet rays, electron beam irradiation, etc., or isocyanate-based compounds (eg, trifunctional isocyanates), organic peroxides, organic metal salts, metal alcoholates, metal chelate compounds, Chemical crosslinking treatment using various crosslinking agents such as a polyfunctional compound (a polyfunctional external crosslinking agent and a polyfunctional monomer for internal crosslinking such as diacrylate, dimethacrylate, etc.) can be carried out. In the case of chemical crosslinking treatment, a crosslinking agent is added to the composition for forming a pressure-sensitive adhesive layer together with the composition of the present invention, the composition for forming a pressure-sensitive adhesive layer is applied to one side of a support or a release treatment side of a release liner, dried, and the drug-containing pressure-sensitive adhesive A layer is formed, a release liner or a support is bonded onto the drug-containing pressure-sensitive adhesive layer, and the laminate is left at 60 to 90° C., preferably 60 to 70° C. for 24 to 48 hours to promote a crosslinking reaction. A drug-containing pressure-sensitive adhesive layer is formed.

In the patch preparation of the present invention, the thickness of the drug-containing pressure-sensitive adhesive layer is not particularly limited, but is preferably 20 to 300 µm, more preferably 30 to 300 µm, and most preferably 50 to 300 µm. When the thickness of the pressure-sensitive adhesive layer is less than 20 μm, it may be difficult to obtain sufficient adhesive strength and to contain an effective amount of the drug. When the thickness of the pressure-sensitive adhesive layer exceeds 300 μm, it may become difficult to form the pressure-sensitive adhesive layer (difficulty in coating).

The support is not particularly limited, and specifically, for example, polyester (eg, poly(ethylene terephthalate) (PET), etc.), nylon, polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polytetra a single film such as fluoroethylene or ionomer resin, or a laminated film of metal foil or two or more films selected from these. In order to improve the adhesion (anchor properties) of the support to the pressure-sensitive adhesive layer, the support is preferably a laminate film of a non-porous film made of the above material and the following porous film, and it is preferable to form a pressure-sensitive adhesive layer on the porous film side. The thickness of the non-porous film is preferably 2 to 100 μm, more preferably 2 to 50 μm.

The porous film is not particularly limited as long as the anchoring property to the pressure-sensitive adhesive layer is improved, and for example, paper, woven fabric, non-woven fabric (eg, polyester (eg, poly(ethylene terephthalate) (PET) non-woven fabric, etc.), mechanical perforation, etc.) (e.g., polyester, nylon, Saran (registered trademark), polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, metal foil, poly a single film such as (ethylene terephthalate) and the like, and a laminate film in which at least one of these is laminated, etc.) and the like can be mentioned. In order to provide the flexibility of the support, in particular, paper, nonwoven fabric, and woven fabric (eg, polyester nonwoven fabric, poly(ethylene terephthalate) nonwoven fabric, etc.) are preferable. When a porous film, for example, a woven or nonwoven fabric is used, the weight thereof is preferably ^{5 to 30 g/m 2 in order to improve anchoring properties.}

The laminate film as a support is produced by a known laminate film manufacturing method such as a dry lamination method, a wet lamination method, an extrusion lamination method, a hot melt lamination method, a co-extrusion lamination method, and the like.

Although the thickness of a support body is not specifically limited, 2-200 micrometers is preferable, and 10-50 micrometers is more preferable. When the thickness is less than 2 mu m, handling properties such as self-supporting properties tend to decrease, and when the thickness exceeds 200 mu m, a sense of incongruity (stiffness) occurs and the followability is often lowered.

Examples of the release liner include a release liner in which a release treatment layer made of a release treatment agent is formed on the surface of a base material for release liner, a plastic film with high releasability itself, and a plastic film with high releasability on the surface of the base material for release liner and a release liner with a release layer formed thereon. The release side of the release liner may be only one side or both sides of the substrate.

In this release liner, the release agent is not particularly limited, and examples thereof include a release agent such as a long-chain alkyl group-containing polymer, silicone polymer (silicone release agent), fluorine-based polymer (fluorine-based release agent) and the like. Examples of the substrate for the release liner include plastic films such as poly(ethylene terephthalate) (PET) films, polyimide films, polypropylene films, polyethylene films, polycarbonate films, polyester (except PET) films, and the like, and these films Metal-deposited plastic film obtained by depositing metal on; papers such as Japanese paper, Western paper, kraft paper, glassine paper, and fine paper; a substrate made of a fibrous material such as a nonwoven fabric or a woven fabric; metal foil and the like.

Examples of the plastic film itself having high releasability include polyethylene (low-density polyethylene, linear low-density polyethylene, etc.), polypropylene, ethylene-α-olefin copolymer (block copolymer or random copolymer) such as polypropylene, ethylene-propylene copolymer, etc.; polyolefins made of polyolefin-based resins composed of a mixture thereof; Teflon (registered trademark) film and the like.

The release layer formed on the surface of the release liner substrate may be formed by laminating or coating the high-peelable plastic film material on the release liner substrate.

The thickness (total thickness) of the release liner is not particularly limited, and is generally 200 µm or less, preferably 25 to 100 µm.

< Reservoir type patch formulation >

2 shows a typical example of the reservoir-type patch formulation of the present invention, wherein the drug storage layer (4), the drug permeation control membrane (3), the pressure-sensitive adhesive layer (2') and the release liner (1) in this order It is laminated|stacked on one side of the support body (5).

In a reservoir-type patch formulation, the composition of the present invention is generally used in a drug storage layer. That is, a drug is added to the composition of the present invention to prepare a drug-containing composition, and this is applied to the drug storage layer. The drug-containing composition may further contain a drug stabilizer, a gelling agent, and the like. In addition, the drug-containing composition may be applied to the drug storage layer by permeating the nonwoven fabric or the like.

Materials, thicknesses, etc. used for the support 5 and the release liner 1 are basically the same as those of the matrix-type patch preparation. As the drug permeation control membrane 3, a microporous membrane having an average pore size of 0.1 to 1 μm can be mentioned. As a material of the microporous membrane, polyolefins such as polypropylene and polyethylene, polytetrafluoroethylene, and the like are used. The thickness of the drug permeation control membrane is generally 1 µm to 200 µm, but 10 µm to 100 µm is particularly preferable from the viewpoints of ease of manufacture and appropriate rigidity.

The drug-containing pressure-sensitive adhesive layer 2 in the matrix-type patch formulation and the pressure-sensitive adhesive layer 2' in the reservoir-type patch formulation are preferably a hydrophobic pressure-sensitive adhesive layer, more preferably a non-aqueous pressure-sensitive adhesive layer, from the viewpoint of skin adhesion. do. Here, the non-aqueous pressure-sensitive adhesive layer is not necessarily limited to completely not containing water, and may contain a small amount of water derived from humidity in the air, skin, and the like. Here, a small amount of water is preferably weight % or less, more preferably 2 weight % or less, and most preferably 1 weight % or less as the moisture content of the laminate of the support and the pressure-sensitive adhesive layer. Here, the moisture content of the laminate of the support and the pressure-sensitive adhesive layer is the weight ratio of water contained in the laminate of the support and the pressure-sensitive adhesive layer (weight of water to the total weight of the laminate of the support and pressure-sensitive adhesive layer), measured by Karl Fischer's coulometric titration method. percentage), specifically as follows. That is, in an environment controlled at a temperature of 23±2° C. and a relative humidity of 40±5% RH, a sample (formulation) is cut into a predetermined size. Since the formulation is usually protected with a release liner, if a release liner is present on the test piece, the release liner is removed and the test piece is placed in a moisture vaporizer. The test piece is heated to 140°C in a water vaporizer, and the water generated by this is introduced into a titration flask using nitrogen as a carrier, and the moisture content (wt%) of the sample is measured by Karl Fischer's coulometric titration method.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but these should not be construed as limiting. In the following description, unless otherwise stated, "parts" or "%" means "parts by weight" or "% by weight".

Examples 1-27 and Comparative Examples 1-15

<Preparation of a composition for promoting percutaneous absorption>

The raw materials in the amounts shown in Tables 1 and 2 were blended, the drug for patch formulation was added above the saturation concentration, and the mixture was stirred. The mixture was filtered through a disposable filter made of polytetrafluoroethylene (PTFE) having a pore diameter of 0.45 µm to prepare a composition for promoting drug transdermal absorption containing the drug at a saturated concentration. As the drug, a basic drug, Zolmitriptan, was used. In the tables, the numerical units are parts by weight.

For the compositions of Examples 1-27 and Comparative Examples 1-15, the following skin permeability test was performed in order to evaluate the effect of accelerating the transdermal absorption of the drug. The results are shown in Tables 3 and 4.

< Skin permeability test >

The skin extracted from the hairless mouse was mounted on a cell for skin permeation experiment (effective area 3 mm?) so that the stratum corneum side became the donor phase and the dermis side became the receptor phase. Phosphate-buffered saline (pH 7.4) was put on the receptor, and a composition for promoting transdermal absorption containing the drug was put on the donor, and a skin permeation experiment was performed at 32°C for 24 hours. After 24 hours, the receptor solution was collected and the drug concentration was measured by high performance liquid chromatography (HPLC).

< HPLC measurement conditions > (ZLM)

Column: Inertsil ODS-3 manufactured by GL Sciences Inc. (particle size 3 μm, inner diameter 3.0 mm × length 75 mm)

Mobile phase: (1 g/L phosphoric acid/50 mM aqueous ammonium acetate solution)/acetonitrile = 85/15

Detection wavelength: 283 nm

Flow rate: 0.45 mL/min

Column temperature: 40°C

Analysis time: 5 minutes

Holding time: 3.0 minutes

The official names of the abbreviations in Table 1 are as showing below.

ZLM: zolmitriptan, PG: propylene glycol, OA: oleyl alcohol

The official names of the abbreviations in Table 2 are as showing below.

ZLM: zolmitriptan, PG: propylene glycol, LA: lauryl alcohol, MA: myristyl alcohol, HDE: hexyldecanol, ODO: octyldodecanol

In Table 3, comparing Example 1 and Comparative Examples 1 to 4, Comparative Example 1 using only propylene glycol (polyhydric alcohol), Comparative Example 2 using only oleyl alcohol (higher alcohol), and propylene glycol and acetic acid (organic acid) In Comparative Example 4 used in combination, the drug permeability was very low, and in Comparative Example 3 using a combination of propylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Examples 1 and 2. In addition, in Example 1 in which propylene glycol, oleyl alcohol and acetic acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Table 3, comparing Example 2 and Comparative Examples 1 to 3 and 5, Comparative Example 1 using only propylene glycol (polyhydric alcohol), Comparative Example 2 using only oleyl alcohol (higher alcohol), and propylene glycol and lactic acid (organic acid) ) was used in combination, the drug permeability was very low, and in Comparative Example 3 using a combination of propylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Examples 1 and 2. In addition, in Example 2, in which propylene glycol, oleyl alcohol and lactic acid were all used in combination, drug permeability was significantly improved, wherein the drug transdermal absorption promoting effect was synergistic due to the combination.

In Table 3, comparing Example 3 and Comparative Examples 1 to 3 and 6, Comparative Example 1 using only propylene glycol (polyhydric alcohol), Comparative Example 2 using only oleyl alcohol (higher alcohol), and propylene glycol and tartaric acid (organic acid) ) was used in combination, the drug permeability was very low, and in Comparative Example 3 using a combination of propylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Examples 1 and 2. In addition, in Example 3 in which propylene glycol, oleyl alcohol and tartaric acid were all used in combination, drug permeability was remarkably improved, where the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Table 3, comparing Example 4 and Comparative Examples 1 to 3 and 7, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 2 using only oleyl alcohol (higher alcohol), the drug permeation amount was very low, In Comparative Example 7 using a combination of propylene glycol and citric acid (organic acid) and Comparative Example 3 using a combination of propylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Examples 1 and 2. In addition, in Example 4, in which propylene glycol, oleyl alcohol and citric acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Table 3, comparing Example 5 and Comparative Examples 1 to 3 and 8, Comparative Example 1 using only propylene glycol (polyhydric alcohol), Comparative Example 2 using only oleyl alcohol (higher alcohol), and propylene glycol and benzoic acid (organic acid) ) was used in combination, the drug permeability was very low, and in Comparative Example 3 using a combination of propylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Examples 1 and 2. In addition, in Example 5 in which propylene glycol, oleyl alcohol and benzoic acid were all used in combination, drug permeability was remarkably improved, where the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Table 3, comparing Example 6 and Comparative Examples 1 to 3 and 9, Comparative Example 1 using only propylene glycol (polyhydric alcohol), Comparative Example 2 using only oleyl alcohol (higher alcohol), and propylene glycol and myristic acid In Comparative Example 9 using (organic acid) in combination, the drug permeation amount was very low, and in Comparative Example 3 using a combination of propylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Examples 1 and 2. In addition, in Example 6 in which propylene glycol, oleyl alcohol and myristic acid were all used in combination, drug permeability was remarkably improved, where the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Table 3, comparing Example 7 and Comparative Examples 1 to 3 and 10, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 2 using only oleyl alcohol (higher alcohol), the drug permeation rate was very low, In Comparative Example 10 using a combination of propylene glycol and isostearic acid (organic acid) and Comparative Example 3 using a combination of propylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Examples 1 and 2. In addition, in Example 7 in which propylene glycol, oleyl alcohol and isostearic acid were all used in combination, drug permeability was remarkably improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Table 3, comparing Example 8 and Comparative Examples 1 to 3 and 11, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 2 using only oleyl alcohol (higher alcohol), the drug permeation amount was very low, In Comparative Example 11 using a combination of propylene glycol and oleic acid (organic acid) and Comparative Example 3 using a combination of propylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Examples 1 and 2. In addition, in Example 8, in which propylene glycol, oleyl alcohol and oleic acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 9 and Comparative Examples 1, 5, and 12, the drug permeation amount in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 5 using propylene glycol and lactic acid (organic acid) in combination This is very low, and in Comparative Example 12 using a combination of propylene glycol and lauryl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 5. In addition, in Example 9, in which propylene glycol, lauryl alcohol and lactic acid were all used in combination, drug permeability was remarkably improved, wherein the drug percutaneous absorption promoting effect was synergistic due to the combination.

In Tables 3 and 4, comparing Example 10 and Comparative Examples 1, 6, and 12, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 6 using a combination of propylene glycol and tartaric acid (organic acid), the drug permeation amount is very low, and in Comparative Example 12 using a combination of propylene glycol and lauryl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 6. In addition, in Example 10, in which propylene glycol, lauryl alcohol and tartaric acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 11 and Comparative Examples 1, 7, and 12, in Comparative Example 1 using only propylene glycol (polyhydric alcohol), the drug permeation amount was very low, but by combining propylene glycol and citric acid (organic acid) In Comparative Example 7 used, drug permeability was promoted. In addition, in Comparative Example 12 using a combination of propylene glycol and lauryl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Example 1. In addition, in Example 11, in which propylene glycol, lauryl alcohol and citric acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 12 and Comparative Examples 1, 8, and 12, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 8 using a combination of propylene glycol and benzoic acid (organic acid), drug permeation amount This is very low, and in Comparative Example 12 using a combination of propylene glycol and lauryl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 8. In addition, in Example 12, in which propylene glycol, lauryl alcohol and benzoic acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 13 and Comparative Examples 1, 11, and 12, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 8 using a combination of propylene glycol and oleic acid (organic acid), the drug permeation amount This is very low, and in Comparative Example 12 using a combination of propylene glycol and lauryl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 8. In addition, in Example 13, in which propylene glycol, lauryl alcohol and oleic acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, when Example 14 and Comparative Examples 1, 5, and 13 are compared, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 5 using a combination of propylene glycol and lactic acid (organic acid), drug permeation amount This is very low, and in Comparative Example 13 using a combination of propylene glycol and myristyl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 5. Further, in Example 14, in which propylene glycol, myristyl alcohol and lactic acid were all used in combination, drug permeability was remarkably improved, wherein the drug transdermal absorption promoting effect was synergistic due to the combination.

In Tables 3 and 4, comparing Example 15 and Comparative Examples 1, 6, and 13, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 6 using a combination of propylene glycol and tartaric acid (organic acid), drug permeation amount This is very low, and in Comparative Example 13 using a combination of propylene glycol and myristyl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 6. Further, in Example 15, in which propylene glycol, myristyl alcohol and tartaric acid were all used in combination, drug permeability was remarkably improved, where the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, when comparing Example 16 and Comparative Examples 1, 7, and 13, in Comparative Example 1 using only propylene glycol (polyhydric alcohol), the drug permeation amount was very low, but by combining propylene glycol and citric acid (organic acid) In Comparative Example 7 and Comparative Example 13 using a combination of propylene glycol and myristyl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Example 1. In addition, in Example 16 in which propylene glycol, myristyl alcohol and citric acid were all used in combination, drug permeability was remarkably improved, wherein the drug percutaneous absorption promoting effect was synergistic due to the combination.

In Tables 3 and 4, comparing Example 17 and Comparative Examples 1, 9, and 13, Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 9 using a combination of propylene glycol and myristic acid (organic acid) The drug permeability was very low, and in Comparative Example 13 using a combination of propylene glycol and myristyl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 9. In addition, in Example 17, in which propylene glycol, myristyl alcohol and myristic acid were all used in combination, drug permeability was significantly improved, where the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 18 and Comparative Examples 1, 10, and 13, in Comparative Example 1 using only propylene glycol (polyhydric alcohol), the drug permeation amount was very low, but propylene glycol and isostearic acid (organic acid) In Comparative Example 10 using a combination and Comparative Example 13 in which propylene glycol and myristyl alcohol (higher alcohol) were used in combination, drug permeability was promoted compared to Comparative Example 1. In addition, in Example 18, in which propylene glycol, myristyl alcohol and isostearic acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 19 and Comparative Examples 1, 11, and 13, in Comparative Example 1 using only propylene glycol (polyhydric alcohol), the drug permeation amount was very low, but by combining propylene glycol and oleic acid (organic acid) In Comparative Example 11 and Comparative Example 13 using a combination of propylene glycol and myristyl alcohol (higher alcohol), drug permeability was promoted compared to Comparative Example 1. In addition, in Example 19, in which propylene glycol, myristyl alcohol and oleic acid were all used in combination, drug permeability was significantly improved, wherein the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 20 and Comparative Examples 1, 5, and 14, the drug permeation amount in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 5 using propylene glycol and lactic acid (organic acid) in combination This is very low, and in Comparative Example 14 using a combination of propylene glycol and hexyldecanol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 5. In addition, in Example 20, in which propylene glycol, hexyldecanol and lactic acid were all used in combination, drug permeability was significantly improved, and the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 21 and Comparative Examples 1, 7, and 14, the drug permeation amount was very low in Comparative Example 1 using only propylene glycol (polyhydric alcohol), but by combining propylene glycol and citric acid (organic acid) In Comparative Example 7 and Comparative Example 14 using a combination of propylene glycol and hexyldecanol (higher alcohol), drug permeability was promoted compared to Comparative Example 1. In addition, in Example 21, in which propylene glycol, hexyldecanol and citric acid were all used in combination, drug permeability was significantly improved, where the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 22 and Comparative Examples 1, 8, and 14, in Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 8 using a combination of propylene glycol and benzoic acid (organic acid), the drug permeation amount This is very low, and in Comparative Example 14 using a combination of propylene glycol and hexyldecanol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 8. In addition, in Example 22, in which propylene glycol, hexyldecanol and benzoic acid were all used in combination, drug permeability was significantly improved, and the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 23 and Comparative Examples 1, 9, and 14, Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 9 using a combination of propylene glycol and myristic acid (organic acid) The drug permeability was very low, and in Comparative Example 14 using a combination of propylene glycol and hexyldecanol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 9. In addition, in Example 23, in which propylene glycol, hexyldecanol and myristic acid were all used in combination, drug permeability was significantly improved, and the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 24 and Comparative Examples 1, 11, and 14, in Comparative Example 1 using only propylene glycol (polyhydric alcohol), the drug permeation amount was very low, but by combining propylene glycol and oleic acid (organic acid) In Comparative Example 11 and Comparative Example 14 using a combination of propylene glycol and hexyldecanol (higher alcohol), drug permeability was promoted compared to Comparative Example 1. In addition, in Example 24, in which propylene glycol, hexyldecanol and oleic acid were all used in combination, drug permeability was significantly improved, and the effect of promoting drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 25 and Comparative Examples 1, 7, and 15, in Comparative Example 1 using only propylene glycol (polyhydric alcohol), the drug permeation amount was very low, but by combining propylene glycol and citric acid (organic acid) In Comparative Example 7 and Comparative Example 15 using a combination of propylene glycol and octyldodecanol (higher alcohol), drug permeability was promoted compared to Comparative Example 1. In addition, in Example 25, in which propylene glycol, octyldodecanol, and citric acid were all used in combination, the effect of accelerating drug transdermal absorption by the combination was found.

In Tables 3 and 4, comparing Example 26 and Comparative Examples 1, 9, and 15, Comparative Example 1 using only propylene glycol (polyhydric alcohol) and Comparative Example 9 using a combination of propylene glycol and myristic acid (organic acid) The drug permeability was very low, and in Comparative Example 15 using a combination of propylene glycol and octyldodecanol (higher alcohol), drug permeability was promoted compared to Comparative Examples 1 and 9. In addition, in Example 26, in which propylene glycol, octyldodecanol and myristic acid were all used in combination, drug permeability was remarkably improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination.

In Tables 3 and 4, comparing Example 27 and Comparative Examples 1, 11, and 15, the drug permeation amount was very low in Comparative Example 1 using only propylene glycol (polyhydric alcohol), but by combining propylene glycol and oleic acid (organic acid) In Comparative Example 11 and Comparative Example 15 using a combination of propylene glycol and octyldodecanol (higher alcohol), drug permeability was promoted compared to Comparative Example 1. In addition, in Example 27, in which propylene glycol, octyldodecanol and oleic acid were all used in combination, drug permeability was remarkably improved, and the effect of promoting drug transdermal absorption was synergistic due to the combination.

Example 28 and Comparative Examples 16-18

<Preparation of a composition for promoting percutaneous absorption>

The raw materials in the amounts shown in Table 5 were blended, the drug for patch formulation was added above the saturation concentration, and the mixture was stirred. The mixture was filtered through a disposable filter made of polytetrafluoroethylene (PTFE) having a pore diameter of 0.45 µm to prepare a composition for promoting drug transdermal absorption containing the drug at a saturated concentration. As the drug, a basic compound, zolmitriptan, was used. In the tables, the numerical units are parts by weight.

For the compositions of Example 28 and Comparative Examples 16 to 18, the above skin permeability test was performed in order to evaluate the effect of accelerating drug transdermal absorption. A result is shown in Table 6.

The official names of the abbreviations in Table 5 are as showing below.

ZLM: zolmitriptan, BG: butylene glycol, OA: oleyl alcohol

In Table 6, comparing Example 28 and Comparative Examples 16 to 18, the drug permeation amount in Comparative Example 16 using only butylene glycol (polyhydric alcohol) and Comparative Example 18 using butylene glycol and isostearic acid (organic acid) in combination Although this was very low, in Comparative Example 17 using a combination of butylene glycol and oleyl alcohol, drug permeability was promoted compared to Comparative Example 16. In addition, in Example 28, in which butylene glycol, oleyl alcohol and isostearic acid were all used in combination, drug permeability was significantly improved, where the effect of accelerating drug transdermal absorption was synergistic due to the combination. From this, it became clear that the combination of polyhydric alcohols, higher alcohols and organic acids can significantly improve the permeability of basic drugs.

Comparative Examples 19-22

<Preparation of a composition for promoting percutaneous absorption>

The raw materials in the amounts shown in Table 7 were blended, the drug for patch formulation was added above the saturation concentration, and the mixture was stirred. The mixture was filtered through a disposable filter made of polytetrafluoroethylene (PTFE) having a pore diameter of 0.45 µm to prepare a composition for promoting drug transdermal absorption containing the drug at a saturated concentration. As the drug, a basic compound, zolmitriptan, was used. In the tables, the numerical units are parts by weight.

The skin permeability test was performed on the compositions of Comparative Examples 19 to 22. A result is shown in Table 8.

The official names of the abbreviations in Table 7 are as showing below.

ZLM: zolmitriptan, IPM: isopropyl myristate, OA: oleyl alcohol

In Table 8, comparing the results of Comparative Examples 19 to 22, in Comparative Example 19 using only isopropyl myristate (fatty acid ester) and Comparative Example 20 using a combination of isopropyl myristate and oleyl alcohol, the drug permeation amount was very low. , Comparative Example 21 using a combination of isopropyl myristate and isostearic acid (organic acid) has improved drug permeability compared to Comparative Example 19. In Comparative Example 22 using isopropyl myristate, oleyl alcohol, and isostearic acid in combination, drug permeability was improved compared to Comparative Example 19 using only isopropyl myristate, but the combination of oleyl alcohol and isostearic acid A synergistic effect of promoting drug transdermal absorption could not be observed. Therefore, from this and the results of Examples 1-28 above, it became clear that the synergistic drug permeability enhancing effect could not be achieved by the combination of the higher alcohol and the organic acid unless the polyhydric alcohol, the higher alcohol and the organic acid were combined.

Example 29 and Comparative Examples 23-25

<Preparation of a composition for promoting percutaneous absorption>

The raw materials in the amounts shown in Table 9 were blended, the drug for patch formulation was added above the saturation concentration, and the mixture was stirred. The mixture was filtered through a disposable filter made of polytetrafluoroethylene (PTFE) having a pore diameter of 0.45 µm to prepare a composition for promoting drug transdermal absorption containing the drug at a saturated concentration. As a drug, propranolol, a basic compound, was used. In the tables, the numerical units are parts by weight.

For the compositions of Example 29 and Comparative Examples 23 to 25, the above skin permeability test was performed in order to evaluate the effect of accelerating drug transdermal absorption. The drug concentration in the receptor solution was measured by HPLC under the following conditions. A result is shown in Table 10.

<HPLC measurement conditions> (PRP)

Column: Inertsil ODS-3 manufactured by GL Sciences Inc. (particle size 3 μm, inner diameter 3.0 mm × length 75 mm)

Mobile phase: phosphate buffer (pH 2.5)/acetonitrile = 70/30

Detection wavelength: 292 nm

Flow rate: 0.40 mL/min

Column temperature: 40°C

Analysis time: 5 minutes

Holding time: 3.2 minutes

The official names of the abbreviations in Table 9 are as showing below.

PRP: propranolol, PG: propylene glycol, OA: oleyl alcohol

In Table 10, comparing Example 29 and Comparative Examples 23 to 25, Comparative Example 25 using a combination of propylene glycol and isostearic acid (organic acid) and Comparative Example using a combination of propylene glycol and oleyl alcohol (higher alcohol) In 24, drug permeability was improved compared to Comparative Example 23 using only propylene glycol (polyhydric alcohol). In addition, in Example 29, in which propylene glycol, oleyl alcohol and isostearic acid were all used in combination, drug permeability was significantly improved, and the effect of promoting drug transdermal absorption was synergistic. From this, it became clear that combining a polyhydric alcohol, a higher alcohol and an organic acid can significantly improve the skin permeability of a basic drug.

Example 30 and Comparative Examples 26-28

<Preparation of a composition for promoting percutaneous absorption>

The raw materials in the amounts shown in Table 11 were blended, the drug for patch formulation was added above the saturation concentration, and the mixture was stirred. The mixture was filtered through a disposable filter made of polytetrafluoroethylene (PTFE) having a pore diameter of 0.45 µm to prepare a composition for promoting drug transdermal absorption containing the drug at a saturated concentration. As a drug, indomethacin, an acidic drug, was used. In the tables, the numerical units are parts by weight.

The composition of Example 30 and Comparative Examples 26 to 28 was subjected to the skin permeability test. The drug concentration in the receptor solution was measured by HPLC under the following conditions. A result is shown in Table 12.

< HPLC measurement conditions > (IND)

Column: Inertsil ODS-3 manufactured by GL Sciences Inc. (particle size 3 μm, inner diameter 3.0 mm × length 75 mm)

Mobile phase: methanol/1 g/L phosphoric acid aqueous solution = 70/30

Detection wavelength: 254 nm

Flow rate: 0.70 mL/min

Column temperature: 40°C

Analysis time: 5 minutes

Holding time: 3.4 minutes

The official names of the abbreviations in Table 11 are as showing below.

IND: indomethacin, PG: propylene glycol, OA: oleyl alcohol

In Table 12, when Example 30 and Comparative Examples 26 to 28 are compared, in Comparative Example 26 using only propylene glycol (polyhydric alcohol) and Comparative Example 28 using a combination of propylene glycol and isostearic acid (organic acid), the drug permeation amount was low. . However, in Comparative Example 27 using a combination of propylene glycol and oleyl alcohol (higher alcohol), drug permeability was improved. In addition, in Example 30 in which propylene glycol, oleyl alcohol and isostearic acid were all used in combination, the effect of accelerating drug transdermal absorption was synergistic due to the combination. From this, it became clear that the effect of accelerating drug transdermal absorption by the combination of a polyhydric alcohol, a higher alcohol and an organic acid is synergistic even with an acidic drug.

<Preparation of patch formulation>

(1) Preparation of acrylic polymer solution

In an inert gas atmosphere, 2-ethylhexyl acrylate (75 parts), N-vinyl-2-pyrrolidone (22 parts), acrylic acid (3 parts) and azobisisobutyronitrile (0.2 parts) were dissolved in ethyl acetate. was added, and solution polymerization was carried out at 60° C. to obtain an acrylic polymer solution (polymer solid content: 28%).

(2) Preparation of polyisobutylene polymer solution

Polymer polyisobutylene (viscosity average molecular weight 4,000,000, Oppanol(R) B200, manufactured by BASF, 22.0 parts as solid content), low molecular weight polyisobutylene (viscosity average molecular weight 55,000, Oppanol(R) B12, manufactured by BASF, solid content 38.0 parts as a content) and an alicyclic saturated hydrocarbon resin (softening point 140° C., ARKON(R) P-140, manufactured by Arakawa Chemical Industries, Ltd., 40.0 parts) were dissolved in toluene to dissolve a polyisobutylene polymer solution (polymer solid content) : 21%) was obtained.

(3) Preparation of patch formulations

Among 100 parts of the composition for patch preparation, 50 parts of propylene glycol is replaced with an acrylic polymer solution containing 49.7 parts of a solid content and 0.3 parts of a crosslinking agent or a polyisobutylene polymer solution containing 50 parts of a solid content of a composition for forming an adhesive layer (coating solution) was obtained. This is coated on one side of a poly(ethylene terephthalate) (hereinafter referred to as PET) film (thickness 75 µm) as a release liner so that the thickness after drying becomes 200 µm, and then dried to form a pressure-sensitive adhesive layer. A PET film (thickness: 2 µm)-PET nonwoven fabric (fabric weight: 12 g/m ² ) laminate is bonded to the pressure-sensitive adhesive layer as a support, and when an acrylic polymer is used, the laminate is aged at 70°C for 48 hours. A process (crosslinking process of an adhesive layer) is carried out, and a laminated sheet is obtained. After cutting the laminated sheet into the shape of a patch preparation, it is packaged in a packaging container in an atmosphere of 3% or less of oxygen concentration, and a patch preparation is obtained. The patch formulation of the present invention exhibits excellent drug transdermal absorption due to the excellent drug transdermal absorption promoting effect of the composition for forming the patch formulation.

Since the composition of the present invention can increase the transdermal absorption of a drug (especially a basic drug), a transdermally absorbable preparation of a drug (especially a basic drug), which has been difficult to formulate due to low transdermal absorption, is formulated by applying the composition of the present invention. can be

This application is based on Japanese Patent Application No. 2013-048450, the content of which is incorporated herein in its entirety.

Claims (10)

A composition for promoting the transdermal absorption of a drug comprising a polyhydric alcohol having 3 to 8 carbon atoms, an organic acid having 2 to 8 carbon atoms and a higher alcohol having 12 to 19 carbon atoms, or an organic acid having 12 to 20 carbon atoms and a higher alcohol having 14 to 20 carbon atoms , wherein the drug is a basic drug, and 100 parts by weight of the total weight of the polyhydric alcohol, the higher alcohol and the organic acid contains 80 to 98 parts by weight of the polyhydric alcohol. The composition according to claim 1, wherein the higher alcohol having 12 to 19 carbon atoms is at least one selected from the group consisting of lauryl alcohol, myristyl alcohol, hexyldecanol and oleyl alcohol. The composition according to claim 1, wherein the higher alcohol having 14 to 20 carbon atoms is at least one selected from the group consisting of myristyl alcohol, hexyldecanol, oleyl alcohol and octyldodecanol. The composition according to any one of claims 1 to 3, which is for a patch formulation. A patch preparation comprising a support and a drug-containing adhesive layer or drug storage layer on one side of the support, wherein the drug-containing adhesive layer or the drug storage layer comprises the composition of any one of claims 1 to 3 and a basic drug A patch formulation that does.
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